Resistance to viral infection involves activation of the innate immune system. An essential component of this response is induction of type 1 interferon (IFN) which in turn induces and activates a cascade of cellular gene products involved in antiviral defense. These induced proteins activate a cellular antiviral state capable of inhibiting diverse viral infections through a wide variety of mechanisms. While the signaling cascade and transcription mechanisms involved in activation of cellular genes in response to IFN treatment have been recently characterized biochemically using cultured cells, the mechanisms responsible for the initial induction of the IFN genes and cell type-specific differences in the response to IFN in vivo are still largely unknown. In particular, while it is clear that induced IFN plays a major role in restricting the spread of influenza virus, it is insufficient to completely prevent infection in the lung while eliminating infection in other tissues. The type 1 IFN gene family contains more than a dozen genes that are divided into two subfamilies, alpha and beta, with the alpha subfamily consisting of at least two groups displaying distinct expression patterns (early and delayed) represented in the mouse by IFNalpha4 (early) and IFNalpha6 (late). While all IFN genes are induced in response to virus, the mechanisms, kinetics, and cell-type specificity of induction are distinct, controlled, at least in part by the transcription factors IFN regulatory factor 3 (IRF3) and IRF7. IRF 7 appears to be required for induction of IFNbeta and IFNalpha4, while IRF7 is essential for the expression of IFNalpha6, modulates the expression of IFNalpha4, and plays, while IRF7 is essential for the expression of IFNalpha6, modulates the expression of IFNalpha4, and plays only a minor role in induction of IFNbeta, IRF3 and IRF7 are controlled at the level of protein abundance, subcellular compartmentalization, DNA binding, and transactivation, all of which are altered by viral infection. Following production of IFN, target cells respond through a second signaling cascade controlled by members of the JAK and STAT families, resulting in induction of antiviral proteins. Whether the different members of the type I IFN family induce distinct antiviral activities is currently unknown. This project will examine the hypothesis that lung is permissive to influenza virus injection due to impaired IFN induction and/or response. The IFN producing and responding cells of the lung, the types of IFN produced, the signaling cascade activated by virus and by IFN, and the induction of antiviral gene products will be characterized in response to fully IFN-responsive cells. These data will increase our understanding of why influenza virus replicates selectively in lung and uncover potential strategies for better controlling viral infection.